NIAID conducts and supports research to prevent, diagnose, and treat infectious and immunological diseases that affect the health of women and girls.
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Composition of Female Genital Tract Microbiome May Affect Risk of HIV Infection
HIV prevalence in young African women is up to eight-fold higher than in young African men, suggesting that biological factors in the female genital tract (FGT) may increase susceptibility to infection. It has previously been hypothesized that certain types of bacteria that naturally colonize the FGT may be linked to decreased rates of HIV infection.
To test this hypothesis, NIAID-funded researchers turned to Females Rising through Education, Support and Health (FRESH), an ongoing trial funded by the Bill & Melinda Gates Foundation. This trial comprises healthy, HIV-uninfected, 18- to 23-year-old black South African women who are provided with intensive HIV prevention counseling and HIV testing. Using genomic sequencing, the scientists studied the assemblage of bacteria and viruses that comprise the reproductive tract microbiota of participants in the FRESH study, and identified four distinct types of FGT bacterial community structures, or cervicotypes. The most prevalent cervicotypes included a diverse collection of bacteria and low levels of Lactobacillus bacteria, a group of bacteria thought to promote vaginal health.
Despite HIV prevention counseling and frequent HIV testing, 31 of 236 women in the study group became infected with HIV during the study. The researchers found that those women who had high-diversity bacterial communities with low Lactobacillus abundance had a four-fold increase in HIV incidence compared with those who had a cervicotype that was dominated by one type of bacterium, Lactobacillus crispatus. High-diversity cervicotypes that included multiple strains of anaerobic bacteria (bacteria that can live without oxygen) also had elevated levels of inflammation-causing proteins that are associated with increased HIV incidence. The presence of Lactobacillus was associated with decreased levels of inflammation and secreted factors that promote inflammation. By contrast, viral community structures did not vary between HIV-infected and uninfected study participants.
In experiments with mice, the researchers showed that the presence of anaerobic bacteria in the FGT increased the numbers of a type of white blood cell in the female reproductive tract that is targeted by HIV, which could increase the risk of HIV infection. Together, the study findings indicate that distinct bacterial types and communities are associated with an increased risk of HIV infection. The results suggest that South African women may be at increased risk of HIV infection based on their reproductive tract microbiota and emphasize the importance of considering the microbiome when developing new approaches to reduce HIV infection.
Reference: Gosmann C et al., Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased HIV Acquisition in Young South African Women, Immunity. 2017 Jan 17; 46: 29–37.
Immune Cell Population May Protect Brain from Lupus Inflammation
Systemic lupus erythematosus (SLE), or lupus, is an autoimmune disorder that disproportionately affects women and is thought to be caused by a combination of genetic and environmental factors. Multiple organs, including the brain, are often affected by SLE disease. Neurological and psychiatric effects can include headaches, problems with basic brain functions (such as memory loss), and mood disorders. Little is known about factors that contribute to SLE-derived brain symptoms, but a recent NIAID-funded study provides new insights.
Using two mouse models of SLE, researchers discovered a subset of immune cells, known as brain-infiltrating CD8+ T cells, that migrate into brain tissue but not many other affected organs and may have protective effects in SLE. CD8+ T cells are normally found circulating in the bloodstream and lymphatic system, but when activated, they can migrate into the tissues to sites of inflammation or infection. The researchers found that brain-infiltrating CD8+ T cells displayed a specific set of protein markers that promote T-cell entry and retention in the tissue. Additionally, brain tissue from lupus-prone mice expressed molecules that could pair with markers on brain-infiltrating CD8+ T cells to help attract and retain these cells in the brain. The function of brain-infiltrating CD8+ T cells is not yet known, but these cells appeared to be beneficial to lupus-prone mice. SLE symptoms, including brain swelling, bleeding, and inflammation, were more severe in lupus-prone mice genetically engineered to lack CD8+ T cells. Together, these results suggest that brain-infiltrating CD8+ T cells may be specifically directed to the brain, perhaps to protect against SLE-related tissue damage.
Reference: Morawski PA et al. Non-pathogenic tissue-resident CD8+ T cells uniquely accumulate in the brains of lupus-prone mice. Sci Rep. 2017 Jan 18;7:40838.
Brd4 Protein May Be Therapeutic Target for Human Papillomavirus
Cervical cancer is the third most common cancer among women and the second most frequent cause of cancer-related deaths worldwide. Nearly all cases of cervical cancer are caused by human papillomaviruses (HPVs), a group of viruses that infect cells called keratinocytes in the outermost layer of skin.
HPVs cannot replicate on their own and must subvert human genes and proteins to drive virus production in infected cells. Because HPV replication is complex, involving successive phases in different layers of skin, it is difficult to reproduce and study in the laboratory. To circumvent this problem, NIAID researchers manufactured HPV-like particles, called HPV quasiviruses, which contain the HPV genome packaged inside a viral shell similar to true HPVs. The researchers then used these HPV pseudoviruses to study the importance of the human cell protein Brd4 in the early stages of HPV infection.
HPV proteins, particularly one called E2, are known to interact with Brd4 in several stages of the viral life cycle, but the importance of Brd4 early in HPV infection is unknown. The researchers created a model infection system that used human keratinocytes genetically manipulated to reduce Brd4 expression. They infected these cells with HPV quasiviruses and found that loss of Brd4 reduced the production of HPV genes and proteins. The researchers also found that Brd4 and the viral protein E2 did not interact during the initial stages of HPV quasivirus replication, suggesting that Brd4 may regulate HPVs using a different mechanism in early-stage versus late-stage infection. These results indicate that Brd4 is integral early in the HPV life cycle and may be a promising therapeutic target for developing measures against HPV infection.
Reference: McKinney CC, et al. B4d4 Activates Early Viral Transcription upon Human Papillomavirus 18 Infection of Primary Keratinocytes. 2016 Nov 22;7(6) e01644-16.
Newly Identified Virulence Factor Helps Listeria monocytogenes Bacteria Infect the Placenta
The bacterium Listeria monocytogenes (Lm) causes a wide variety of diseases that range from a mild infection of the digestive tract that causes gastrointestinal distress in healthy people to bacterial meningitis, a life-threatening disease that causes swelling of tissues surrounding the brain and spinal cord, in people who have weakened immune systems. Lm is a significant health threat to pregnant women and their unborn children, as infection with this microbe during pregnancy frequently leads to premature delivery and stillbirth.
Despite the serious health risk that infections pose to both mother and unborn child during pregnancy, little is known about the delicate balance the maternal immune system must maintain, both to ensure that the fetus is not seen as “foreign” and attacked by maternal immune cells and to protect it from pathogens. The unique immune relationship between mother and fetus and the relatively high resistance of the placenta to infection by microbes led NIAID-funded researchers to hypothesize that Lm may produce specific molecules, called virulence factors, that enable it to infect the placenta.
The researchers discovered one Lm gene that produces a newly identified virulence factor, InlP. The virulence factor strongly promoted infection of the placenta by Lm in mouse and guinea pig models of Lm infection, but played only a minor role in Lm infection of other maternal organs that were examined. The results suggest that InlP is a virulence factor that helps Lm overcome the placenta’s function as a natural immune barrier against microbes.
InlP may provide a new tool for further study of microbial interactions with the maternal immune system and placenta and could eventually lead to new interventions for the prevention or treatment of infection-related complications in pregnancy.
Citation: Faralla C et al. InlP, a New Virulence Factor with Strong Placental Tropism. Infect Immun. 2016 Nov 18;84(12):3584-96.
Antibody Protects Against Fetal Abnormalities in Mouse Model of Zika Virus Infection
Recent epidemics of Zika virus infection in South and Central America have caused international concern because infection of pregnant women can cause miscarriage and serious birth defects, including microcephaly (an unusually small head). In rare cases, Zika virus infection in adults may also lead to Guillain-Barré syndrome—an autoimmune disorder that causes temporary or even permanent nerve damage. Developing measures to defend against and treat this rapidly emerging infectious disease is a high priority, as no specific therapies or vaccine for Zika virus currently exist.
To develop possible therapies for Zika virus infection, NIAID-supported researchers isolated 29 distinct antibodies from immune cells of three people who were previously infected with Zika virus. The researchers found one antibody, ZIKV-117, that neutralized all types of Zika virus tested, including African, Asian, and American strains. They then assessed the therapeutic potential of ZIKV-117 in pregnant and non-pregnant mice infected with Zika virus.
Giving a single dose of ZIKV-117 to Zika virus-infected male mice with weakened immune systems up to 5 days after infection protected the mice from death, as compared with mice treated with a control antibody. Treating pregnant mice with ZIKV-117 before infection with Zika virus reduced virus levels in the placenta and in the fetal brain and improved fetal survival and health relative to Zika virus-infected pregnant mice that did not receive the antibody. Additionally, administering ZIKV-117 to pregnant mice immediately after they were infected with Zika virus yielded similar results.
This study suggests that ZIKV-117 treatment can reduce transmission of Zika virus from mother to fetus, treat active Zika virus infection, and improve pregnancy outcomes in Zika-infected mice. The findings could contribute to the development of therapies for people infected with Zika virus and may also inform the design of vaccines that can elicit potent protective antibodies against the virus.
Reference: Sapparapu G et al. Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice. Nature. 2016 Dec 15;540(7633):443-447.